Copenhagen Workshop May 2014

Lynda Paleshnuik | May 20141

Copenhagen Workshop May 2014

Quality assessment principles

Part IIL. Paleshnuik

Lead Quality Assessor

PQT


Overview

• FPP sections of the dossier - General considerations

• Tips for assessing stability studies

• Example FPP issues • Excipients • Questionable information

• Finalizing the assessment report


General considerations

The applicant must:

• Develop the product appropriately (PD talk)

• Show evidence of the product developed (data on pilot/primary batches)

• Fully describe the intended production batches i.e. scale-up (batch records talk)


General considerations

• Demonstrate the ability to control the product now (COAs) and in the future (specifications talk yesterday)

• Validate the scale-up (PV talk later today)

• Demonstrate the stability of the product (stability talk later today) in the proposed pack (previous talk)


General considerationsAssessors must:

• Show that all the above have been accomplished in the detailed report.

Finalization of the report will be covered later in this talk.


Tips for stability studies


Stability studiesStability is one of the most complex parts of the assessment

The talk later today will give the overview of how the studies should be done.

Some tips follow to make the assessment smoother


Tips regarding stability - #1Demonstration of the stability of the product

Usually at least 24 month shelf-life is proposed.

BUT

Only a small amount of stability data is required to be in the original dossier (6 months data, 3 months in exceptions (e.g. RH, 2nd line TB for PQ).


Assessors must ensure they always have the most updated data during the review. This means:

• Checking the dates of the study to ensure currentdata was provided (1-2 months required to compile/submit for a station)

• Requesting available updated data in each round of questions.

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Tips regarding stability - #1


Tips regarding stability - #1Requesting updated stability:

• Often this is forgotten, multiple assessment rounds with no request for updated data, and either:

• Request comes at the end, when all other significant issues are resolved, or

• Request is never sent, and the product is approved/accepted without review of the available data - poor

practice



• Extrapolation of the shelf-life should not be automatic. If the applicant does not propose it, do not offer/grant it.

• If the applicant proposes it, only grant it if the data truly supports it. (ICH Q1E)


Tips regarding stability - #3The very best stability summaries can fail when…

… the assessor does not carefully read over their own summary….

… and fails to note an obvious issue.



• Specifications commonly change over the course of the assessment process, but the stability data does not incorporate the change

• This means the product gets to the approval stage but there is no data on certain parameters



• Now we must settle for data at the last station only, or on retained samples past the shelf-life

• We lose the benefit of multi-station data that would show trends

Include current limits in the stability summary each time stability is reviewed


Tips regarding stability - #4Stability summaryAppearance (Blue round biconvex tablets…) ConformsDissolution (NLT 80%(Q) in 30 minutes) lowest individual value 88.3%, no trendRelated compounds A (NMT 0.2%) up to 0.13%, no trend B (NMT 0.3%) up to 0.22%, increasing trend Individual unknowns (NMT 0.2%) up to 0.13%, no trend Sum (NMT 0.6%) up to 0.37%, no trend… etc…


Tips regarding stability - #5Stability conditions

Overlooked deficiency:

• Long-term stability conditions are incorrect in the stability protocol (e.g. protocol states 25ºC/60%)

Seems minor, but this can mean inadequate future testing of the production batches



Alu-Alu blisters

• Advantage: do not need a demonstration of moisture permeability or light transmission

• However, Alu-Alu blisters are not magical.


Tips regarding stability - #6Alu-Alu blisters

• The protective ability depends on:

• thickness

• pinholes

• sealing process



• Do not assume that a change from HDPE bottles to Alu-Alu blisters means a more protective package that does not need its own stability studies

• I have seen numerous examples where stability is better in HDPE bottles, and in Alu-Alu had to be below 25°C



• WHO PQ variation GL (TRS981) provides a good example of how to consider changes, including a change to Al-Al

• GL states, “demonstrated equivalent or more protective packaging”

• This means, don’t make assumptions


Example issues


Example issues - Issue #1


Example issues - Issue #1Excipients: risk-benefit decisions can be made to reduce assessment:

Excipients meeting an accepted compendial standard:

Can accept the declaration of standard* (e.g. NF) in lieu of:

Specifications Certificates of Analysis

* Assumes the current standard will be adopted


Example issues - Issue #1BUT…

In-house (IH) standards always require more attention.

Common in-house standard: Opadry film-coating excipients

Main consideration: Ensure IR identity is included in the IH specifications.


Example issues - Issue #1In-house standards always require more attention.

What if it is an IH standard for a common excipient, do these require more attention?


Example issues - Issue #1Real example #1: an IH excipient was not looked at carefully and the ramifications could have been serious.

Dosage form: Dispersible tabletExcipients: included some less common excipients, e.g. mannitol, aspartame, saccharin sodium and monoammonium glycyrrhizinate (MAG).First issue: the above were not discussed in the report


Example issues - Issue #1Consider two sources:

Excipient handbook: “applications (normal use and concentration), “incompatibilities”, “comments”

European Commission GL: “Excipients in the label and package leaflet of medicinal products for human use”



Less common excipients: The report should have mentioned, at minimum, whether these excipients are flagged by the European Commission GL:

“The Annex provides a list of the excipients which should be stated on the labeling and outlines the information which should appear in the package leaflet, for these excipients.”



Quality assessor’s responsibility:

Identify excipients flagged in the EC GL, AND

Label: ensure excipients are declared on the label as per EC GL

SmPC section 2: ensure excipients above are listed

PIL: send the general comment for the excipients above: "Due to the contents of xx in the formulation, a specific warning/precautionary statement may have to be included in the product information. This will be provided with the draft WHOPAR, including the WHO recommended product information, at a later stage."


Example issues - Issue #1Recall:

Excipients: included less common excipients mannitol, aspartame, saccharin sodium and monoammonium glycyrrhizinate (MAG).


Example issues - Issue #1In this case, mannitol and aspartame are listed in the GL.

Mannitol: to be declared on the label if > 10 g (N/A)

Aspartame: to be declared on the label always (zero threshold), and PIL statement indicated (left to WHOPAR stage): “Contains a source of phenylalanine. May be harmful for people with phenylketonuria.”

None of the other excipients are mentioned in the EC GL.


Example issues - Issue #1First issue: not discussing non-common excipients

Second issue: an IH standard is declared for MAG.The specifications were reviewed, tests listed in the report, and a request went out to include an identity test in the specs. However,

A compendial monograph exists, therefore a comparison must be made/discussed.


Example issues - Issue #1At the QA stage, assessors were asked to make this comparison.

Outcome: BP or NF limits were not met.

The QA comment went out, to revise the specifications to conform to BP or NF limits.


Example issues - Issue #1The applicant responded that the excipient is not actually MAG.

It is a mixture of MAG, maltose and ethyl maltol.

And interestingly, MAG is not even the main component, which is maltose (about 80%).


Example issues - Issue #1This raises three new concerns.

1. The applicant has not fully declared the composition of the tablets. This could be deliberate (to hide a problematic excipient) (to avoid issues with a non-compendial excipient), or due to lack of experience with stringent regulations.

2. Ethyl maltol is an uncommon excipient.


Example issues - Issue #13. We need to look carefully at maltose, in case they were trying to avoid declaring it. (This is a concern because a mixture of mainly maltose was called MAG, a minor component of the mixture)


Example issues - Issue #1We must learn more about ethyl maltol.

We check the recognized compendia: there is no monograph in the recognized compendia.

We check the excipient handbook for uses and concentrations and incompatibilities.

Nothing unusual comes up. (Flavourant used at the proposed concentrations, no relevant incompatibilities)


Example issues - Issue #1We must look closely at maltose.

Maltose is a well-known excipient and they are declaring NF standard.

There are no warnings regarding maltose in the EC excipient GL.

The excipient handbook has no cautions for the amount used, the use, or compatibility.


Example issues

The API in this product is also sensitive to problems with excipients (absorption can be affected).

A consultation/search had to be done for any record of issues with the API and maltose or ethyl maltol.

No issues were identified.


Example issues - Issue #1Comment to applicant

It is noted that you did not previously disclose the composition of the mixture <Tradename>. It is of critical importance that the full quantitative formulation of each product be declared in the dossier, QOS-PD and QIS. The only exception is many-component flavourants, for which the quantitative formulation can be separately provided in the dossier or by reference to a DMF, but need not be declared in the QOS-PD and QIS. Note that section P.1 b) ii) of the QIS and QOS-PD states, “Composition of all components purchased as mixtures” and should have included the composition of this mixture. In addition, as monoammonium glycyrrhizinate is not the main component of this mixture, it should preferably be identified in the formulation as “maltose mixture ([Tradename])”, with all components and their relative percentages listed below the formulation tables in the QIS.


Example issues - Issue #1The comment goes on to ask for revised blank manufacturing records and product information, that correctly identifies the product composition.


Example issues - Issue #1The applicant responds with the revised documents that fully declare the composition.

We could find no indication that this was a deliberate omission, and it is considered to be due to inexperience (this is the applicant’s first dossier in PQ).


Example issues - Issue #1Conclusion: what could have happened in such a situation, if the IH standard had not been looked into?

A company could be “hiding” the presence of excipients in a product by declaring one excipient instead of a mixture. This could lead to issues with the product after approval.

In such a case, it would be hard to defend how the regulators had not observed this. The fact that the excipient did not meet standards of a compendial monograph was the clue that it was not really the excipient claimed.



Handling questionable data, or

What to do when the data (or applicant’s responses to questions) don’t add up

Lynda Paleshnuik | March 201424


Real example #2: In the course of the QA, the credibility/truthfulness of the data came into question.

The applicant made confirmatory statements that were later found to be incorrect, and provided data that seemed too good to be true.



Dossier is an FDC containing a critically low solubility API

Reliable data is critical for such a product.

Assessors have spent rounds trying to set appropriate PSD limits, based on the API lots used in the biobatch



Example 1: Applicant confirms:

“Please find enclosed the COAs of the API manufactured by the same manufacturing process, including purification steps and milling/micronization step, as that of the biolot API”.

The bold point was critical for the review.

The lots are later found to be manufactured by a significantly different manufacturing process.



Example 2: in the response to our request for PSD results for BE lots, they respond in November 2012:

“Kindly note that for COA generation, the API lots used in the biobatch is not available.”

But suddenly in December 2013, to resolve the issue, they are able to test these API lots for PSD and provide the results.



The approach during QA was to include the following comment to the applicant:

It is noted that in your response dated 5 November 2012 you stated, "Kindly note that for COA generation, the API lots used in the bio batch is not available." You are requested to explain how you have obtained data on these lots.



Response:

In Nov 2012, we informed you that there was no material from the API lots used in biobatch to re-analyze and generate COA. However we didn’t consider the existing histogram from initial analysis. Now we have taken PSD data (at D10 and D50) from the histograms generated during initial analysis and reported the results.



This suggests that they have no remaining material and no new data…

…but they also provided data generated December 2013.

We could ask how they got this… but they are likely to say they tested retained samples of the lots.

IF they are being untruthful, they will tell us what we want to hear.



But confidence in the answers is now low, and if there IS an issue, further detailed questions would give them too much information on our concerns.



NOTE: this was presented as an example to assessors, and the following was emphasized:

In this situation:

1. Don’t show all your cards - in case there IS an issue, don’t give away exactly what is being looked at

2. Stay professional. They are innocent until proven otherwise, and we never have all the data.



The matter was taken to the inspectorate.

An inspection was conducted end of March 2014.

Conclusion: the data was acceptable. It turned out that the BE lot data was always available, the lot was available for testing the issue was actually:

A lack of communication between those responding to dossier questions, and the API unit responsible for test results



Concerns about accuracy, correctness, credibility of the data should be clearly noted in the report.


Finalizing the report


Finalizing the Assessment Report

Two important aspects:

• Writing good comments to the applicant

• Finalizing the report


Finalizing the Assessment Report - Comments

Writing good comments:

Good comments can save time in the assessment of the responses, by being:

• Clear

• Comprehensive

• Including a summary of changes in official documents (putting the burden on the applicant)

May 2014 L Paleshnuik59


Be comprehensive - include the minimum requirements: Example: packaging specifications were not provided

for HDPE bottles.

The minimum requirement is that specifications (from the FPP packager – generally the applicant or FPP manufacturer) include a specific test for identification.

A vague question will result in a vague/incomplete response. The ideal question will result in a response that is complete the first time.



Poor question: You are requested to provide packaging specifications for the HDPE bottles.

Possible Response to this question: Applicant provides supplier specifications, not the required applicant/ manufacturer specifications, and/or identification testing is not included.

A follow-up question is necessary.



Good question: You are requested to provide [FPP packager] packaging specifications for the HDPE bottles. Specifications should include a test for identification by a specific method such as IR.

If a response will not be accepted without some element, that element should be included in the question.

This is particularly important when the requirement is not spelt out in the guidance documents.

A comprehensive comment also helps the next assessor review the response.



Avoid questions where the door is open to an unacceptable result.

Example: Please justify why there was no limit on individual impurities in the FPP specifications.

They will try to justify this. There is no justification for not meeting a requirement.

The comment should be worded clearly, “Your specifications should be revised to include a limit on individual impurities in the FPP specifications.”



Include declarative statements when revised signed documents are requested, for example for revised methodology, blank production records, stability protocols, etc:

“Your response should include the revised document with the change history or a statement that no other changes have been made.”The onus is now on the applicant to confirm changes made. This can save time, avoids unsolicited changes sneaking in.Note: change histories should not be relied on for specifications, a new version should ALWAYS be compared to the previous version assessed.



Whenever possible, comments should include references to published guidelines (WHO guidelines, where possible, in PQ).Be able to justify your questions. The reason should be in the question (data is missing, data is incomplete, clarify confusing data, data suggests a related quality issue, etc). A long or complicated reason should be clearly stated in the assessment report.



Summarizing/finalizing the final report is a critical aspect of the assessment

This takes some timeThe assessment may have taken place over daysand had many interruptionsand distractions.



Finalization should be done in one sitting in order to get the full picture and:

Avoid inconsistencies in the report. Observe new issues only apparent when all

aspects are complete



Conclusions should be substantiated Be prepared to defend your conclusions Guidelines are usually relevant, but there are

always exceptions if scientific justification is provided


Summary

• FPP sections of the dossier - General considerations

• Tips for assessing stability studies

• Example FPP issues • Excipients • Questionable information

• Finalizing the assessment report


Thank you

Copenhagen Workshop May 2014

Documents

Transcript of Copenhagen Workshop May 2014